OVERALL DESCRIPTION: (from the application) This application for a Mentored Research Scientist Development Award is designed to provide the principle investigator with additional training in the biology of aging and physical inactivity. Applicant: The applicant's primary area of research interest is vascular biology. The immediate goal of the applicant is to gain additional training in molecular biology. The long-term goal of the applicant is to develop an independent research program focusing on the molecular mechanisms for the detrimental effects of aging and physical inactivity on vascular function. In addition, the molecular basis for the beneficial effects of exercise training in ameliorating the effects of age and physical inactivity will be studied. Career Development/Traininq Plan: The training plan of this proposal consists of two primary elements: 1.) the acquisition of new skills in molecular biology that can be applied to physiological studies, and 2.) structured activities including formal training in research ethics; participation in journal clubs and seminar series; presentations at scientific meetings; and weekly, mentoring sessions with the applicant's sponsor. Research Plan: The purpose of this investigation is to determine the mechanism(s) responsible for the endothelial dysfunction associated with aging. Particular emphasis will be placed on testing hypotheses concerning the role of endothelial nitric oxide synthase (eNOS) in regulating vascular reactivity in young and old rats. The general hypothesis is that endothelial dysfunction associated with aging and physical inactivity is due to a down-regulation of eNOS gene expression in vascular endothelium throughout the arterial network in skeletal muscle. The specific aims of this application are to: 1.) Determine the mechanisms responsible for impaired endothelium mediated vascular responses in senescent rats, 2.) Determine the mechanism of flow/shear stress regulation of eNOS gene expression in arteries and arterioles of senescent rats, 3.) Determine whether over expression of eNOS in blood vessels will enhance endothelial function in senescent rats, and 4.) Determine the efficacy of exercise training in inducing eNOS gene expression and enhancing endothelial function in senescent rats. Environment: The proposed studies will be conducted at the Dalton Cardiovascular Research Center and the Department of Veterinary Biomedical Sciences at the University of Missouri. The sponsor, M. Harold Laughlin, Ph.D., is an established investigator and mentor in the field of vascular exercise physiology. The Co-Sponsor, Elmer M. Price, Ph.D., is an established investigator in the field of molecular biology. The consulting mentor, Donald D. Heistad, M.D., is a recognized expert in the field of vascular molecular biology.